Publications by authors named "Margaret Green"

58 Publications

Acute Rheumatic Fever: A Review of Essential Cutaneous and Histological Findings.

Cureus 2021 Jan 8;13(1):e12577. Epub 2021 Jan 8.

Dermatopathology, Joint Pathology Center, Silver Spring, USA.

Acute rheumatic fever (ARF) is an autoimmune response that may occur after infection with group A . Clinical manifestations are protean, making the syndrome difficult to recognize in the 21st century. Secondary prophylaxis with benzathine penicillin is given for 10 years after an episode of ARF to prevent recurrence and reduce the risk of rheumatic heart disease. This case highlights the importance of providing a detailed clinical history to the dermatopathologist when considering ARF in the differential diagnosis.
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http://dx.doi.org/10.7759/cureus.12577DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7870119PMC
January 2021

Tocilizumab in hospitalized patients with COVID-19: Clinical outcomes, inflammatory marker kinetics, and safety.

J Med Virol 2021 04 22;93(4):2270-2280. Epub 2020 Nov 22.

Department of Medicine, University of Washington, Seattle, Washington, USA.

Coronavirus disease 2019 (COVID-19) due to infection with severe acute respiratory syndrome coronavirus 2 causes substantial morbidity. Tocilizumab, an interleukin-6 receptor antagonist, might improve outcomes by mitigating inflammation. We conducted a retrospective study of patients admitted to the University of Washington Hospital system with COVID-19 and requiring supplemental oxygen. Outcomes included clinical improvement, defined as a two-point reduction in severity on a six-point ordinal scale or discharge, and mortality within 28 days. We used Cox proportional-hazards models with propensity score inverse probability weighting to compare outcomes in patients who did and did not receive tocilizumab. We evaluated 43 patients who received tocilizumab and 45 who did not. Patients receiving tocilizumab were younger with fewer comorbidities but higher baseline oxygen requirements. Tocilizumab treatment was associated with reduced C-reactive protein, fibrinogen, and temperature, but there were no meaningful differences in time to clinical improvement (adjusted hazard ratio [aHR], 0.92; 95% confidence interval [CI], 0.38-2.22) or mortality (aHR, 0.57; 95% CI, 0.21-1.52). A numerically higher proportion of tocilizumab-treated patients had subsequent infections, transaminitis, and cytopenias. Tocilizumab did not improve outcomes in hospitalized patients with COVID-19. However, this study was not powered to detect small differences, and there remains the possibility for a survival benefit.
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http://dx.doi.org/10.1002/jmv.26674DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7753799PMC
April 2021

QT interval and arrhythmic safety of hydroxychloroquine monotherapy in coronavirus disease 2019.

Heart Rhythm O2 2020 Aug 11;1(3):167-172. Epub 2020 Jun 11.

Division of Cardiology, University of Washington, Seattle, Washington.

Background: Observational studies have suggested increased arrhythmic and cardiovascular risk with the combination use of hydroxychloroquine (HCQ) and azithromycin in patients with coronavirus disease 2019 (COVID-19).

Objective: The arrhythmic safety profile of HCQ monotherapy, which remains under investigation as a therapeutic and prophylactic agent in COVID-19, is less established and we sought to evaluate this.

Methods: In 245 consecutive patients with COVID-19 admitted to the University of Washington hospital system between March 9, 2020, and May 10, 2020, we identified 111 treated with HCQ monotherapy. Patients treated with HCQ underwent a systematic arrhythmia and QT interval surveillance protocol including serial electrocardiograms (ECG) (baseline, following second HCQ dose). The primary endpoint was in-hospital sustained ventricular arrhythmia or arrhythmic cardiac arrest. Secondary endpoints included clinically significant QTc prolongation.

Results: A total of 111 patients with COVID-19 underwent treatment with HCQ monotherapy (mean age 62 ± 16 years, 44 women [39%], serum creatinine 0.9 [interquartile range 0.4] mg/dL). There were no instances of sustained ventricular arrythmia or arrhythmic cardiac arrest. In 75 patients with serial ECGs, clinically significant corrected QT (QTc) prolongation was observed in a minority (n = 5 [7%]). In patients with serial ECGs, there was no significant change in the QTc interval in prespecified subgroups of interest, including those with prevalent cardiovascular disease or baseline use of renin-angiotensin-aldosterone axis inhibitors.

Conclusions: In the context of a systematic monitoring protocol, HCQ monotherapy in hospitalized COVID-19 patients was not associated with malignant ventricular arrhythmia. A minority of patients demonstrated clinically significant QTc prolongation during HCQ therapy.
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http://dx.doi.org/10.1016/j.hroo.2020.06.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7289101PMC
August 2020

Clinical Features and Outcomes of 105 Hospitalized Patients With COVID-19 in Seattle, Washington.

Clin Infect Dis 2020 11;71(16):2167-2173

Department of Medicine, University of Washington, Seattle, Washington, USA.

Background: Washington State served as the initial epicenter of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic in the United States. An understanding of the risk factors and clinical outcomes of hospitalized patients with coronavirus disease 2019 (COVID-19) may provide guidance for management.

Methods: All laboratory-confirmed COVID-19 cases in adults admitted to an academic medical center in Seattle, Washington, between 2 March and 26 March 2020 were included. We evaluated individuals with and without severe disease, defined as admission to the intensive care unit or death.

Results: One hundred five COVID-19 patients were hospitalized. Thirty-five percent were admitted from a senior home or skilled nursing facility. The median age was 69 years, and half were women. Three or more comorbidities were present in 55% of patients, with hypertension (59%), obesity (47%), cardiovascular disease (38%), and diabetes (33%) being the most prevalent. Most (63%) had symptoms for ≥5 days prior to admission. Only 39% had fever in the first 24 hours, whereas 41% had hypoxia at admission. Seventy-three percent of patients had lymphopenia. Of 50 samples available for additional testing, no viral coinfections were identified. Severe disease occurred in 49%. Eighteen percent of patients were placed on mechanical ventilation, and the overall mortality rate was 33%.

Conclusions: During the early days of the COVID-19 epidemic in Washington State, the disease had its greatest impact on elderly patients with medical comorbidities. We observed high rates of severe disease and mortality in our hospitalized patients.
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http://dx.doi.org/10.1093/cid/ciaa632DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7314181PMC
November 2020

African Tick-Bite Fever.

Am J Med 2020 09 20;133(9):1051-1053. Epub 2020 Apr 20.

Department of Infectious Diseases, Walter Reed National Military Medical Center, Bethesda, Md.

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http://dx.doi.org/10.1016/j.amjmed.2020.03.031DOI Listing
September 2020

Compassionate Use of Remdesivir for Patients with Severe Covid-19.

N Engl J Med 2020 06 10;382(24):2327-2336. Epub 2020 Apr 10.

From Cedars-Sinai Medical Center, Los Angeles (J.G.), El Camino Hospital, Mountain View (D.S., D. Chelliah), Sutter Santa Rosa Regional Hospital, Santa Rosa (G.G.), Regional Medical Center (A.S., J.R.) and Good Samaritan Hospital (S.M.), San Jose, John Muir Health, Walnut Creek (J.B.), UC Davis Health, Sacramento (S.H.C.), NorthBay Medical Center, Fairfield (S.I.), and Gilead Sciences, Foster City (A.O.O., A.D., Y.Z., L.Z., A. Chokkalingam, E.E., L. Telep, L. Timbs, I.H., S.S., H.C., S.K.T., L.W., P.D., R.M., A.G., R.P.M., D.M.B.) - all in California; the National Center for Global Health and Medicine, Tokyo (N.O.), Tokyo Bay Urayasu Ichikawa Medical Center, Urayasu City (R.O.), Hiratsuka City Hospital, Hiratsuka (K.Y.), Yokohama City University Hospital, Yokohama (H.K.), Gunma University Hospital, Gunma (T.M.), and Tosei General Hospital, Seto (Y.M.) - all in Japan; Providence Regional Medical Center Everett, Everett (G.D.), and University of Washington Medical Center-Northwest (M.L.G.) and Virginia Mason Medical Center (S. Chihara), Seattle - all in Washington; Fondazione IRCCS Policlinico San Matteo, Pavia (E.A.), IRCCS, San Raffaele Scientific Institute (A. Castagna) and Azienda Socio Sanitaria Territoriale Spedali (ASST) Santi Paolo e Carlo, Department of Health Services, University of Milan (A.D.M.), Milan, National Institute for Infectious Diseases, IRCCS, L. Spallanzani, Rome (E.N.), Università degli Study of Brescia, ASST Civili di Brescia, Brescia (E.Q.-R.), San Gerardo Hospital, ASST Monza, University of Milan-Bicocca, Monza (G.L.), and Azienda Unite Sanitarie Locali-IRCCS, Reggio Emilia (M.M.) - all in Italy; Universitätsklinikum Düsseldorf, Düsseldorf, Germany (T. Feldt); Université de Paris, Infection, Antimicrobiens, Modélisation, Evolution (IAME), INSERM, and Assistance Publique-Hôpitaux de Paris, Department of Infectious Diseases, Bichat Hospital, Paris (F.-X.L.), Centre Hospitalier Régional et Universitaire de Brest-La Cavale Blanche, Brest (E.L.), and Division of Infectious Diseases and Tropical Medicine, University Hospital of Bordeaux, Bordeaux (D.N.) - all in France; St. Alexius Medical Center, Hoffman Estates, IL (S.A.); Mackenzie Health, Richmond Hill, ON, Canada (D. Chen); Columbia University Irving Medical Center, New York (J.C.); Hospital Universitario La Paz-Carlos III, Instituto de Investigación Hospital Universitario La Paz, Madrid (M.M.-R.); Bernhoven Hospital, Uden, the Netherlands (E.V.); Kaiser Franz Josef Hospital, Vienna (A.Z.); the U.S. Public Health Service Commissioned Corps, Washington, DC (R.C.); and Miriam Hospital, Providence, RI (T. Flanigan).

Background: Remdesivir, a nucleotide analogue prodrug that inhibits viral RNA polymerases, has shown in vitro activity against SARS-CoV-2.

Methods: We provided remdesivir on a compassionate-use basis to patients hospitalized with Covid-19, the illness caused by infection with SARS-CoV-2. Patients were those with confirmed SARS-CoV-2 infection who had an oxygen saturation of 94% or less while they were breathing ambient air or who were receiving oxygen support. Patients received a 10-day course of remdesivir, consisting of 200 mg administered intravenously on day 1, followed by 100 mg daily for the remaining 9 days of treatment. This report is based on data from patients who received remdesivir during the period from January 25, 2020, through March 7, 2020, and have clinical data for at least 1 subsequent day.

Results: Of the 61 patients who received at least one dose of remdesivir, data from 8 could not be analyzed (including 7 patients with no post-treatment data and 1 with a dosing error). Of the 53 patients whose data were analyzed, 22 were in the United States, 22 in Europe or Canada, and 9 in Japan. At baseline, 30 patients (57%) were receiving mechanical ventilation and 4 (8%) were receiving extracorporeal membrane oxygenation. During a median follow-up of 18 days, 36 patients (68%) had an improvement in oxygen-support class, including 17 of 30 patients (57%) receiving mechanical ventilation who were extubated. A total of 25 patients (47%) were discharged, and 7 patients (13%) died; mortality was 18% (6 of 34) among patients receiving invasive ventilation and 5% (1 of 19) among those not receiving invasive ventilation.

Conclusions: In this cohort of patients hospitalized for severe Covid-19 who were treated with compassionate-use remdesivir, clinical improvement was observed in 36 of 53 patients (68%). Measurement of efficacy will require ongoing randomized, placebo-controlled trials of remdesivir therapy. (Funded by Gilead Sciences.).
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http://dx.doi.org/10.1056/NEJMoa2007016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7169476PMC
June 2020

A phase 1 study of azacitidine with high-dose cytarabine and mitoxantrone in high-risk acute myeloid leukemia.

Blood Adv 2020 02;4(4):599-606

Comprehensive Cancer Center.

In this phase 1 study, azacitidine (AZA) was given before high-dose cytarabine (HiDAC) and mitoxantrone (mito) based on the hypothesis that epigenetic priming with a hypomethylating agent before cytotoxic chemotherapy would improve response rates in patients with high-risk acute myeloid leukemia (AML), including relapsed/refractory disease. The primary objective was to establish the recommended phase 2 dose of AZA given before standard HiDAC/mito. In a dose escalation scheme, 46 patients (median age, 66 years) received AZA at 37.5, 50, or 75 mg/m2 subcutaneously or IV once daily on days 1 to 5 followed by HiDAC (3000 mg/m2) and mitoxantrone (30 mg/m2) once each on days 6 and 10 (the HiDAC/mito dose was reduced 33% in elderly subjects). Two dose-limiting toxicities occurred (both in the same patient): acute liver failure and kidney injury at the 50 mg/m2 dose. The 30-day induction death rate was 2.2% (1 of 46). The overall response rate, including complete remission and complete remission with incomplete count recovery, was 61% (28 of 46). Previously untreated patients aged ≥60 years with therapy-related AML and de novo AML were more likely to respond than untreated patients with AML progressing from an antecedent hematologic disorder (myelodysplastic syndrome and chronic myelomonocytic leukemia). Patients with favorable European Leukemia Network risk (P = .008), NPM1 mutations (P = .007), or IDH2 mutations (P = .03) were more likely to respond, and those with TP53 mutations (P = .03) were less likely to respond. The recommended phase 2 dose of AZA is 75 mg/m2 per day on days 1 to 5 followed by HiDAC (3000 mg/m2) and mitoxantrone (30 mg/m2) once each on days 6 and 10. This trial was registered at www.clinicaltrials.gov as #NCT01839240.
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http://dx.doi.org/10.1182/bloodadvances.2019000795DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7042987PMC
February 2020

Cytomegalovirus Humoral Response Against Epithelial Cell Entry-Mediated Infection in the Primary Infection Setting After Hematopoietic Cell Transplantation.

J Infect Dis 2020 04;221(9):1470-1479

Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.

Background: The influence of humoral immunity on the prevention of primary cytomegalovirus (CMV) infection after hematopoietic cell transplantation (HCT) is poorly understood.

Methods: To determine whether neutralizing antibodies (nAbs) against CMV pentameric complex (PC)-mediated epithelial cell entry decrease CMV infection after HCT, samples were analyzed from a randomized controlled trial of CMV intravenous immunoglobulin (IVIG) prophylaxis. Weekly serum from 61 CMV donor-positive/recipient-negative (D+/R-) HCT patients (33 control, 28 CMV IVIG) was tested using a PC-entry nAb assay and quantitative CMV polymerase chain reaction (PCR).

Results: There was a trend toward higher weekly PC-entry nAb titers (P = .07) and decreased CMV infection by PCR at viral load cutoffs of ≥1000 and ≥10 000 IU/mL in the CMV IVIG arm. High nAb titers were not significantly protective against CMV infection later after HCT in both study arms. Among CMV-infected patients, each log2 increase in nAb titer was associated with an average 0.2 log10 decrease in concurrent CMV viral load after infection (P = .001; adjusted for study arm).

Conclusions: This study provides initial support that CMV IVIG prophylaxis moderately enhances PC-entry nAB activity in D+/R- HCT recipients.
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http://dx.doi.org/10.1093/infdis/jiz596DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7137890PMC
April 2020

Lichen Nitidus.

J Am Osteopath Assoc 2019 Oct;119(10):704

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http://dx.doi.org/10.7556/jaoa.2019.119DOI Listing
October 2019

A Co-Located Continuity Clinic Model to Address Healthcare Needs of Women Living Unhoused With Opioid Use Disorder, Who Engage in Transactional Sex in North Seattle.

Sex Transm Dis 2020 01;47(1):e5-e7

From the Division of Infectious Diseases, Department of Medicine.

This is a review of the first 50 patients attending a colocated continuity clinic with harm reduction services to women experiencing homelessness in north Seattle. Among those tested, patients had high rates of curable sexually transmitted infections (44%), injection opioid use (36%), transactional sex (69%), unintended pregnancy (10%), and human immunodeficiency virus infections (10%).
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http://dx.doi.org/10.1097/OLQ.0000000000001064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6923540PMC
January 2020

Prospective Assessment of Cytomegalovirus Immunity in High-Risk Donor-Seropositive/Recipient-Seronegative Liver Transplant Recipients Receiving Either Preemptive Therapy or Antiviral Prophylaxis.

J Infect Dis 2019 07;220(5):752-760

Department of Medicine, University of Washington, Seattle.

The differential impact of preemptive therapy (PET) and antiviral prophylaxis (AP) on development of cytomegalovirus (CMV)-specific neutralizing antibody (nAb) and T-cell responses have not previously been directly compared in high-risk donor-seropositive/recipient-seronegative (D+R-) organ transplant recipients. We prospectively assessed T-cell and nAb responses 3 months after transplantation in cohorts of high-risk D+R- liver transplant recipients who received either PET (n = 15) or AP (n = 25) and a control group of CMV-seropositive transplant recipients (R+) (AP; n = 24). CMV phosphoprotein 65 (pp65)- and immediate early protein 1-specific multifunctional T-cell responses were determined by means of intracellular cytokine staining and nAbs against BADrUL131-Y4 CMV in adult retinal pigment epithelial cell line-19 human epithelial cells; nAbs were detected in 8 of 12 (67%) in the PET group, none of 17 in the AP group, and 20 of 22 (91%) in the R+ group. Multifunctional CD8 and CD4 T-cell responses to pp65 were generally similar between PET and R+ groups, and lower for the AP group; multifunctional CD4 responses were similar across all groups. Among D+R- liver transplant recipients, PET was associated with the development of greater nAb and multifunctional CD8 T-cell responses compared with AP, providing a potential mechanism to explain the relative protection against late-onset disease with PET. Future studies are needed to define specific immune parameters predictive of late-onset CMV disease with AP.
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http://dx.doi.org/10.1093/infdis/jiz181DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7325329PMC
July 2019

Co-expression and prognostic significance of putative CSC markers CD44, CD133, wild-type EGFR and EGFRvIII in metastatic colorectal cancer.

Oncotarget 2019 Mar 1;10(18):1704-1715. Epub 2019 Mar 1.

School of Life Sciences, Pharmacy and Chemistry, Kingston University London, Kingston, UK.

The presence of colorectal cancer stem cells (CSCs) have been associated with tumour initiation and resistance to therapy. This study investigated the co-expression and prognostic significance of the CSCs biomarkers CD44 and CD133 with wild-type EGFR (wtEGFR) and EGFRvIII in colorectal cancer (CRC). The expression of these biomarkers were determined in tumours from 70 patients with metastatic CRC by immunohistochemistry, and in a panel of human CRC cell lines, and their variants with acquired-resistance to EGFR inhibitors, by flow cytometry. The expression of CD44, CD133, wtEGFR and EGFRvIII were present in 17%, 23%, 26% and 13% of cases and the co-expression of CD44/CD133 with wtEGFR and EGFRvIII were present in 9% and 3% of the cases respectively. Only co-expression of CSCs/EGFRvIII ( = 0.037), and amphiregulin ( = 0.017) were associated with worse overall survival. Interestingly, disease-free survival was improved in BTC expressing patients ( = 0.025). CD133 expression and its co-expression with CD44 were associated with primary-resistance to irinotecan and acquired-resistance to anti-EGFR inhibitors respectively. Our results suggest co-expression of CSCs and EGFRvIII could be potential biomarkers of worse overall survival and resistance to therapy in patients with mCRC and warrants further validation in a larger cohort.
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http://dx.doi.org/10.18632/oncotarget.26722DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6422200PMC
March 2019

Cytomegalovirus shedding from breastmilk and mucosal sites in healthy postpartum women: A pilot study.

J Med Virol 2019 05 3;91(5):894-898. Epub 2019 Jan 3.

Departments of Medicine and Laboratory Medicine, University of Washington, Seattle, WA.

Mother-to-child cytomegalovirus (CMV) breastmilk transmission can occur in the postnatal period. In a pilot study, we measured daily CMV detection by polymerase chain reaction in breastmilk, vaginal, and saliva samples from nine healthy CMV-seropositive postpartum women for 28 days. CMV was found in seven of nine women and 171 of 253 breastmilk samples (67.6%). In four women, all breastmilk samples were positive. CMV was less frequently detected in the vagina (39 of 258, 15.1%) and saliva (53 of 258, 20.5%). Daily breastmilk, oral, and genital collection is feasible and demonstrates high variability between women. Further study of the dynamics of CMV in distinct anatomic compartments is warranted.
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http://dx.doi.org/10.1002/jmv.25386DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6402967PMC
May 2019

Washington state satellite HIV clinic program: a model for delivering highly effective decentralized care in under-resourced communities.

AIDS Care 2018 09 31;30(9):1120-1127. Epub 2018 May 31.

a Division of Allergy and Infectious Diseases , University of Washington , Seattle , WA , USA.

To improve access to high-quality HIV care in underserved regions of Western Washington (WA) State, we collaborated with the WA State Department of Health (DOH) and community partners to launch four satellite HIV clinics. Here, we describe this innovative clinical care model, present an estimate of costs, and evaluate patient care outcomes, including virologic suppression rates. To accomplish this, we assessed virologic suppression rates 12 months before and 12 months after the satellite clinics opened, comparing people living with HIV (PLWH) who enrolled in the satellite clinics versus all PLWH in the same regions who did not. We also determined virologic suppression rates in 2015 comparing satellite clinic versus non-satellite clinic patients and compared care quality indicators between the satellite clinics and the parent academic clinic. Results demonstrate that the change in virologic suppression rate 12 months before to 12 months after the satellite clinics opened was higher for patients who enrolled in the satellite clinics compared to all those in the same region who did not (18% versus 6%, p < 0.001). Virologic suppression in 2015 was significantly higher for satellite clinic than non-satellite clinic patients at three of four sites. Care quality indicators were met at a high level at the satellite clinics, comparable to the parent academic clinic. Overall, through community partnerships and WA DOH support, the satellite clinic program increased access to best practice HIV care and improved virologic suppression rates in difficult-to-reach areas. This model could be expanded to other regions with inadequate access to HIV practitioners, though financial support is necessary.
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http://dx.doi.org/10.1080/09540121.2018.1481194DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6334292PMC
September 2018

Treatment of Corticosteroid-Induced Hypopigmentation Using Fractional Carbon Dioxide Laser.

Dermatol Surg 2019 02;45(2):298-300

Dermatology Department, Naval Medical Center San Diego, San Diego, California Dermatology Department, Hospital Americano Base Naval de Rota, Cádiz, Spain.

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http://dx.doi.org/10.1097/DSS.0000000000001548DOI Listing
February 2019

Co-expression and prognostic significance of the HER family members, EGFRvIII, c-MET, CD44 in patients with ovarian cancer.

Oncotarget 2018 Apr 13;9(28):19662-19674. Epub 2018 Apr 13.

School of Life Sciences, Pharmacy and Chemistry, Kingston University London, Kingston, UK.

EGFR and HER-2 are important targets but none of the monoclonal antibodies or small molecule tyrosine kinase inhibitors specific for the HER members has been approved for the treatment of patients with ovarian cancers. In some studies, co-expression of other growth factor receptors has been associated with resistance to therapy with the HER inhibitors. The aim of the present study was to determine the relative expression, cellular location, and prognostic significance of HER-family members, the EGFR mutant (EGFRvIII) c-MET, IGF-1R and the cancer stem cell biomarker CD44 in 60 patients with FIGO stage III and IV ovarian cancer. At cut off >5% of tumour cells with positive staining, 62%, 59%, 65% and 45% of the cases were EGFR, HER-2, HER-3 and HER-4 positive, and 3%, 22% and 48.3% of the cases were positive for EGFRvIII, c-MET, and CD44 respectively. Interestingly, 23% co-expressed all four members of the HER family. On univariate analysis, only EGFR staining at >50% of tumour cells (HR = 3.57, = 0.038) and CD44 staining at 3+ intensity (HR = 7.99, = 0.004) were associated with a poorer overall survival. EGFR expression (HR = 2.83, = 0.019) and its co-expression with HER-2, HER-3, HER-2/HER-3, and c-MET were all associated with poorer disease-free survival. Our results suggest co-expression of the HER-family members is common in Stage III and IV ovarian cancer patients. Further studies on the prognostic significance and predictive value of all HER family member proteins for the response to treatment with various forms of the HER inhibitors are warranted.
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http://dx.doi.org/10.18632/oncotarget.24791DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5929416PMC
April 2018

WT1 peptide vaccine in Montanide in contrast to poly ICLC, is able to induce WT1-specific immune response with TCR clonal enrichment in myeloid leukemia.

Exp Hematol Oncol 2018 11;7. Epub 2018 Jan 11.

1Section of Hematology/Oncology, Department of Medicine, University of Chicago Medical Center, 5841 S. Maryland, MC 2115, Chicago, IL 60637-1470 USA.

Background: The optimal strategy for vaccination to induce CD8 T cell responses against WT1 is not known.

Methods: A pilot randomized study in HLA-A02 patients to receive vaccination with WT1 in Montanide or in poly ICLC, a TLR3 agonist, to explore the novel immune adjuvant was conducted. Seven patients were randomized. Four patients received WT1 in Montanide, and three with WT1 in poly ICLC. Five patients were in morphologic remission and two had residual morphologic disease at the study entry.

Results: All patients finished the induction phase without any major toxicity except mild transient local injection reaction. One patient on the Montanide arm developed aseptic ulceration at two vaccine sites which healed without antibiotics. Three of 4 patients on the Montanide arm had a decreased expression of WT1 after WT1 vaccination, and two of them demonstrated generation of WT1-specific cytotoxic CD8 T cell responses with biased TCR beta chain enrichment. In contrast, no obvious WT1-specific immune responses were detected in two patients on the poly ICLC arm, nor was there clonal enrichment by TCR alpha/beta sequencing; however, these patients did also have decreased WT1 expression and remained in remission several years after the initiation of treatment.

Conclusions: WT1 peptide vaccine with Montanide as an adjuvant induces detectable WT1-specific CD8 T cell responses with clonal TCR enrichment, which may be capable of controlling leukemia recurrence in the setting of minimal residual disease. Poly ICLC may induce anti-leukemic activity in the absence of detectable WT1 specific CD8 T cell responses. NCT01842139, 7/3/2012 retrospectively registered; https://clinicaltrials.gov/ct2/show/NCT01842139.
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http://dx.doi.org/10.1186/s40164-018-0093-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5765712PMC
January 2018

A phase I study of selinexor in combination with high-dose cytarabine and mitoxantrone for remission induction in patients with acute myeloid leukemia.

J Hematol Oncol 2018 01 5;11(1). Epub 2018 Jan 5.

Department of Medicine, Section of Hematology/Oncology, University of Chicago Medicine, 5841 S. Maryland, MC 2115, Chicago, IL, 60637-1470, USA.

Background: Novel therapies for patients with acute myeloid leukemia (AML) are imperative, particularly for those with high-risk features. Selinexor, an exportin 1 (XPO1/CRM1) inhibitor, has demonstrated anti-leukemia activity as a single agent, as well as in combination with anthracyclines and/or DNA-damaging agents.

Methods: We report the findings of a phase I dose escalation trial with cohort expansion in 20 patients with newly diagnosed or relapsed/refractory AML that combined selinexor with age-adjusted high-dose cytarabine and mitoxantrone (HiDAC/Mito).

Results: Three (15%) patients received the initial dose of 60 mg of selinexor (~ 35 mg/m), and 17 (85%) received the target level of 80 mg (~ 50 mg/m). No dose-limiting toxicities were observed. Common adverse events included febrile neutropenia (70%), diarrhea (40%), anorexia (30%), electrolyte abnormalities (30%), bacteremia (25%), cardiac toxicities (25%), fatigue (25%), and nausea/vomiting (25%). None were unexpected given the HiDAC/Mito regimen. Serious adverse events occurred in 6 (30%) patients; one was fatal. Ten (50%) patients achieved a complete remission (CR), 3 (15%) achieved CR with incomplete recovery (CRi), 1 (5%) achieved partial remission (PR), and 6 (30%) had progressive disease for an overall response rate (ORR) of 70%. Eight of 14 (57%) responders proceeded to allogeneic stem cell transplantation. Correlative studies of WT1 levels showed persistently detectable levels in patients who either did not respond or relapsed quickly after induction.

Conclusion: The selinexor/HiDAC/Mito regimen is feasible and tolerable at selinexor doses of 80 mg/day (~ 50 mg/m/day) twice weekly. The recommended phase II dose is 80 mg and warrants further study in this combination.

Trial Registration: ClinicalTrials.gov , NCT02573363 . Registered October 5, 2015.
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http://dx.doi.org/10.1186/s13045-017-0550-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5756334PMC
January 2018

Infectious complications of CD19-targeted chimeric antigen receptor-modified T-cell immunotherapy.

Blood 2018 01 16;131(1):121-130. Epub 2017 Oct 16.

Department of Medicine, University of Washington, Seattle, WA.

Lymphodepletion chemotherapy with CD19-targeted chimeric antigen receptor-modified T (CAR-T)-cell immunotherapy is a novel treatment for refractory or relapsed B-cell malignancies. Infectious complications of this approach have not been systematically studied. We evaluated infections occurring between days 0 to 90 in 133 patients treated with CD19 CAR-T cells in a phase 1/2 study. We used Poisson and Cox regression to evaluate pre- and posttreatment risk factors for infection, respectively. The cohort included patients with acute lymphoblastic leukemia (ALL; n = 47), chronic lymphocytic leukemia (n = 24), and non-Hodgkin lymphoma (n = 62). There were 43 infections in 30 of 133 patients (23%) within 28 days after CAR-T-cell infusion with an infection density of 1.19 infections for every 100 days at risk. There was a lower infection density of 0.67 between days 29 and 90 ( = .02). The first infection occurred a median of 6 days after CAR-T-cell infusion. Six patients (5%) developed invasive fungal infections and 5 patients (4%) had life-threatening or fatal infections. Patients with ALL, ≥4 prior antitumor regimens, and receipt of the highest CAR-T-cell dose (2 × 10 cells per kg) had a higher infection density within 28 days in an adjusted model of baseline characteristics. Cytokine release syndrome (CRS) severity was the only factor after CAR-T-cell infusion associated with infection in a multivariable analysis. The incidence of infections was comparable to observations from clinical trials of salvage chemoimmunotherapies in similar patients. This trial was registered at www.clinicaltrials.gov as #NCT01865617.
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http://dx.doi.org/10.1182/blood-2017-07-793760DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5755046PMC
January 2018

Infectious complications of CD19-targeted chimeric antigen receptor-modified T-cell immunotherapy.

Blood 2018 01 16;131(1):121-130. Epub 2017 Oct 16.

Department of Medicine, University of Washington, Seattle, WA.

Lymphodepletion chemotherapy with CD19-targeted chimeric antigen receptor-modified T (CAR-T)-cell immunotherapy is a novel treatment for refractory or relapsed B-cell malignancies. Infectious complications of this approach have not been systematically studied. We evaluated infections occurring between days 0 to 90 in 133 patients treated with CD19 CAR-T cells in a phase 1/2 study. We used Poisson and Cox regression to evaluate pre- and posttreatment risk factors for infection, respectively. The cohort included patients with acute lymphoblastic leukemia (ALL; n = 47), chronic lymphocytic leukemia (n = 24), and non-Hodgkin lymphoma (n = 62). There were 43 infections in 30 of 133 patients (23%) within 28 days after CAR-T-cell infusion with an infection density of 1.19 infections for every 100 days at risk. There was a lower infection density of 0.67 between days 29 and 90 ( = .02). The first infection occurred a median of 6 days after CAR-T-cell infusion. Six patients (5%) developed invasive fungal infections and 5 patients (4%) had life-threatening or fatal infections. Patients with ALL, ≥4 prior antitumor regimens, and receipt of the highest CAR-T-cell dose (2 × 10 cells per kg) had a higher infection density within 28 days in an adjusted model of baseline characteristics. Cytokine release syndrome (CRS) severity was the only factor after CAR-T-cell infusion associated with infection in a multivariable analysis. The incidence of infections was comparable to observations from clinical trials of salvage chemoimmunotherapies in similar patients. This trial was registered at www.clinicaltrials.gov as #NCT01865617.
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http://dx.doi.org/10.1182/blood-2017-07-793760DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5755046PMC
January 2018

Viral Pneumonia in Patients with Hematopoietic Cell Transplantation and Hematologic Malignancies.

Authors:
Margaret L Green

Clin Chest Med 2017 06;38(2):295-305

University of Washington, 1959 NE Pacific Street, Box 359930, Seattle, WA 98195, USA; Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Seattle, WA 98109, USA. Electronic address:

Viral pneumonia is a common complication for patients with hematologic malignancies and after hematopoietic cell transplantation causing significant morbidity, and often mortality. Infections are predominantly caused by herpes viruses, either by reactivation of latent infection, or less commonly primary infection, or community respiratory viruses. High-resolution CT scan is useful for diagnosis but is nonspecific; generally, bronchoalveolar lavage is required. Prevention strategies are not pathogen-specific but include vaccination, chemoprophylaxis, preemptive treatment, and effective infection-prevention strategies during community outbreaks. Directed antiviral treatment is available for some pathogens. Toxicities and viral resistance are perennial challenges.
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http://dx.doi.org/10.1016/j.ccm.2016.12.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7115723PMC
June 2017

A MULTICENTER, LONGITUDINAL, INTERVENTIONAL, DOUBLE BLIND RANDOMIZED CLINICAL TRIAL IN HEMATOPOIETIC CELL TRANSPLANT RECIPIENTS RESIDING IN REMOTE AREAS: LESSONS LEARNED FROM THE LATE CYTOMEGALOVIRUS PREVENTION TRIAL.

Contemp Clin Trials Commun 2016 Dec 5;4:84-89. Epub 2016 May 5.

Vaccine and Infectious Disease, Fred Hutchinson Cancer Research Center, Seattle, Washington; Clinical Research Divisions, Fred Hutchinson Cancer Research Center, Seattle, Washington; Medicine, University of Washington, Seattle, Washington.

Purpose: The logistics of conducting double-blinded phase III clinical trials with participants residing in remote locations are complex. Here we describe the implementation of an interventional trial for the prevention of late cytomegalovirus (CMV) disease in hematopoietic cell transplantation (HCT) subjects in a long-term follow-up environment.

Methods: A total of 184 subjects at risk for late CMV disease surviving 80 days following allogeneic HCT were randomized to receive six months of valganciclovir or placebo. Subjects were followed through day 270 post-transplant at their local physician's office within the United States. Anti-viral treatment interventions were based on CMV DNAemia as measured by polymerase chain reaction (PCR) (>1000 copies/mL) and granulocyte colony stimulating factor (G-CSF) was prescribed for neutropenia (absolute neutrophil count (ANC <1.0 × 10 cells/L). Blood samples for viral testing and safety monitoring were shipped to a central laboratory by overnight carrier. Real-time communication was established between the coordinating center and study sites, primary care physicians, and study participants to facilitate starting, stopping and dose adjustments of antiviral drugs and G-CSF. The time required to make these interventions was analyzed.

Results: Of the 4169 scheduled blood specimens, 3832 (92%) were received and analyzed; the majority (97%) arriving at the central site within 2 days. Among subjects with positive CMV DNAemia (N=46), over 50% received open label antiviral medication within one day. The median time to start G-CSF for neutropenia was <1 day after posting of laboratory results (range 0-6; N=38). Study drug dose adjustments for abnormal renal function were implemented 203 times; within one day for 48% of cases and within 2 days for 80% of cases.

Conclusion: Complex randomized, double-blind, multicenter interventional trials with treatment decisions made at a central coordinating site can be conducted safely and effectively according to Good Clinical Practice (GCP) guidelines over a large geographic area.
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http://dx.doi.org/10.1016/j.conctc.2016.05.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5292623PMC
December 2016

The impact of co-expression of wild-type EGFR and its ligands determined by immunohistochemistry for response to treatment with cetuximab in patients with metastatic colorectal cancer.

Oncotarget 2017 Jan;8(5):7666-7677

School of Life Sciences, Pharmacy and Chemistry, Kingston University London, Kingston UK.

Anti-EGFR mAbs cetuximab and panitumumab are routinely used for the treatment of patients with KRAS-wild type metastatic colorectal cancer (mCRC). However, in some patients their efficacy remains modest and with no clear association between the EGFR protein expression determined by PharmDx™ kit, and response to anti-EGFR therapies. Therefore, we investigated the relative expression and predictive value of wild-type EGFR (wtEGFR), mutated EGFRvIII and EGFR ligand proteins in mCRC patients treated with cetuximab. The expression levels of wtEGFR, EGFRvIII, and EGFR ligand were determined by immunohistochemistry (IHC) in 60 tumour specimens using specific antibodies. Sections were scored according to the percentage of positive tumour cells, intensity and cellular location of staining, and these were associated with response, overall survival (OS) and progression-free survival (PFS). At cut-off value > 5%, wtEGFR, and EGFRvIII were present in 44%, and 41%, betacellulin (BTC) in 72%, followed by epigen (67%), TGFα (58%), amphiregulin (34%), EGF (31%) of the cases, respectively and 96% of the wtEGFR positive cases had co-expression of at least one ligand. We found a significant association between the expression of wtEGFR and poor response to cetuximab. In addition, the co-expression of wtEGFR with one ligand at a cut-off value of > 5% and > 10% was associated with worse response to cetuximab (P = 0.021, and P = 0.005 respectively). We found a 3-fold and 5-fold increased risk of shorter OS with expression of BTC and epigen. Interestingly, the expression of wtEGFR and its co-expression with one or two ligands was associated with shorter PFS but not with OS. The relative expression of wtEGFR and its competing ligands, which is the target for therapeutic interventions with anti-EGFR antibodies, could serve as a more reliable predictive biomarker of response to therapy with anti-EGFR mAbs in mCRC patients and warrants further investigation in large prospective studies.
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http://dx.doi.org/10.18632/oncotarget.13835DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5352351PMC
January 2017

Cytomegalovirus viral load and mortality after haemopoietic stem cell transplantation in the era of pre-emptive therapy: a retrospective cohort study.

Lancet Haematol 2016 Mar 20;3(3):e119-27. Epub 2016 Feb 20.

Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA; Department of Medicine, University of Washington, Seattle, WA, USA; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.

Background: Although cytomegalovirus viral load is commonly used to guide pre-emptive therapy in the post-transplantation setting, few data are available correlating viraemia with clinical endpoints. We therefore investigated the association between cytomegalovirus viral load and mortality in the first year after haemopoietic stem cell transplantation.

Methods: In this retrospective cohort study, we included patients from the Fred Hutchinson Cancer Research Center, WA, USA, who received an allogeneic haemopoietic stem cell transplantation between Jan 1, 2007, and Feb 28, 2013, were cytomegalovirus seropositive or had a seropositive donor, and underwent weekly plasma cytomegalovirus monitoring by PCR through to day 100 post-transplantation. Cox proportional hazards models were used to estimate the association of cytomegalovirus viral load at different thresholds with overall mortality by 1 year post-transplantation, adjusting for the use of pre-emptive therapy and other factors such as neutropenia, and graft-versus-host disease.

Findings: Of the 1037 patients initially selected for inclusion in this cohort, 87 (8%) patients were excluded because of missing cytomegalovirus testing and 24 (2%) were excluded because of their participation in cytomegalovirus prophylaxis trials. In the remaining 926 patients included in this study, the cumulative overall mortality was 30·0% (95% CI 26·9-33·0) 1 year after haemopoietic stem cell transplantation. 95 patients developed cytomegalovirus disease; death was directly attributable to cytomegalovirus disease in three (1%) of 263 patients who died in the first year after transplantation. A cytomegalovirus viral load of 250 IU/mL or greater was associated with increased risk of early (day 0-60 post-transplantation) death (adjusted hazard ratio [HR] 19·8, 95% CI 9·6-41·1). The risk was attenuated after day 60 (adjusted HR 1·8, 95% CI 1·3-2·3). Similar associations were noted for higher cytomegalovirus viral load thresholds.

Interpretation: Cytomegalovirus viraemia is associated with an increased risk of overall mortality in the first year after haemopoietic stem cell transplantation, independent of the use of pre-emptive therapy, and with evidence of a positive dose-response relationship. These data indicate the suitability of viral load as a surrogate clinical endpoint for clinical trials for cytomegalovirus vaccines, biologics, and drugs.

Funding: Merck and Co, National Institutes of Health.
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http://dx.doi.org/10.1016/S2352-3026(15)00289-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4914379PMC
March 2016

Patient Preferences Comparing Linear Versus Purse String Closures in Dermatologic Surgery Utilizing a Novel Simulator-Based Educational Tool.

Dermatol Surg 2015 Sep;41(9):1030-7

*Dermatology Department, Walter Reed National Military Medical Center, Bethesda, Maryland.

Background: Patients often query in regard to cosmetic outcomes after cutaneous surgery. This study provides information on this topic by surveying preference on 2 skin closure methods, purse and linear. The authors used a novel method to poll opinions by incorporating simulated skin within the context of the survey.

Objective: To determine patient's preference for linear or purse string closure. Additional outcomes were to survey patient's opinions regarding which scar characteristics have the highest cosmetic impact, the cosmetic importance of a scar, and the utility of simulators, and patient photographs as methods of understanding closure techniques.

Materials And Methods: Participants were prospectively recruited to complete a survey. Data outcomes were analyzed using descriptive statistics and the chi-square test of association.

Results: About half of the participants (54.7%) preferred linear closure. Preference was independent of gender (p = .90) or having a prior linear or purse string closure (p = .17). Patient photographs were the most influential for determining preference according to 86.2% of participants; however, 88% of the participants found simulator devices useful for educational purposes.

Conclusion: The methods in this survey may represent a venue for educating patients and incorporating their preferences into the choices they will make regarding dermatologic procedures, which they will undergo.
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http://dx.doi.org/10.1097/DSS.0000000000000460DOI Listing
September 2015

Smoking and mortality--beyond established causes.

N Engl J Med 2015 05;372(22):2168-9

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http://dx.doi.org/10.1056/NEJMc1503675DOI Listing
May 2015

Effectiveness and safety of lower dose prednisone for initial treatment of acute graft-versus-host disease: a randomized controlled trial.

Haematologica 2015 Jun 14;100(6):842-8. Epub 2015 Feb 14.

Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA University of Washington, Seattle, WA, USA.

We conducted a phase III study to test the hypothesis that initial therapy with "lower dose" prednisone is effective and safe for patients with newly diagnosed acute graft-versus-host disease. We hypothesized that a 50% decrease in the initial dose of prednisone for treatment of acute graft-versus-host disease would suffice to control graft-versus-host disease without increasing the incidence of secondary treatment. Patients with grade IIa manifestations (upper gastrointestinal symptoms, stool volumes <1.0 L/day, rash involving <50% of the body surface, no hepatic dysfunction; n=102) were randomized to start treatment with prednisone at 1 mg/kg/day or 0.5 mg/kg/day. Those with grade IIb or higher manifestations (rash involving ≥50% of the body surface, stool volumes ≥1.0 L/day or hepatic involvement; n=62) were randomized to start treatment with prednisone at 2 mg/kg/day or 1 mg/kg/day. The primary study end point (a ≥33% relative reduction of the mean cumulative prednisone dose by day 42 after initial treatment with lower dose prednisone) was not reached. With a median follow up of 36 months (range 7-53), initial treatment with lower dose prednisone appeared to be effective for patients presenting with grade IIa manifestations since it did not increase the likelihood of requiring secondary immunosuppressive therapy. Further exploratory analyses suggested that for patients presenting with skin-predominant grade IIb or higher manifestations, initial treatment with lower dose prednisone was associated with an increased risk of requiring secondary immunosuppressive therapy (41% vs. 7%; P=0.001). In summary, initial treatment of newly diagnosed acute graft-versus-host disease with lower dose prednisone is effective. Within the statistical limitations of the study, results showed no suggestion that initial use of lower dose prednisone adversely affected survival.
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http://dx.doi.org/10.3324/haematol.2014.118471DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4450631PMC
June 2015

Molecular diagnostic tools for detection and differentiation of phytoplasmas based on chaperonin-60 reveal differences in host plant infection patterns.

PLoS One 2014 31;9(12):e116039. Epub 2014 Dec 31.

Agriculture and Agri-Food Canada, Saskatoon Research Centre, Saskatoon, Saskatchewan, Canada.

Phytoplasmas ('Candidatus Phytoplasma' spp.) are insect-vectored bacteria that infect a wide variety of plants, including many agriculturally important species. The infections can cause devastating yield losses by inducing morphological changes that dramatically alter inflorescence development. Detection of phytoplasma infection typically utilizes sequences located within the 16S-23S rRNA-encoding locus, and these sequences are necessary for strain identification by currently accepted standards for phytoplasma classification. However, these methods can generate PCR products >1400 bp that are less divergent in sequence than protein-encoding genes, limiting strain resolution in certain cases. We describe a method for accessing the chaperonin-60 (cpn60) gene sequence from a diverse array of 'Ca.Phytoplasma' spp. Two degenerate primer sets were designed based on the known sequence diversity of cpn60 from 'Ca.Phytoplasma' spp. and used to amplify cpn60 gene fragments from various reference samples and infected plant tissues. Forty three cpn60 sequences were thereby determined. The cpn60 PCR-gel electrophoresis method was highly sensitive compared to 16S-23S-targeted PCR-gel electrophoresis. The topology of a phylogenetic tree generated using cpn60 sequences was congruent with that reported for 16S rRNA-encoding genes. The cpn60 sequences were used to design a hybridization array using oligonucleotide-coupled fluorescent microspheres, providing rapid diagnosis and typing of phytoplasma infections. The oligonucleotide-coupled fluorescent microsphere assay revealed samples that were infected simultaneously with two subtypes of phytoplasma. These tools were applied to show that two host plants, Brassica napus and Camelina sativa, displayed different phytoplasma infection patterns.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0116039PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4281212PMC
October 2015

A phase I and pharmacodynamic study of the histone deacetylase inhibitor belinostat plus azacitidine in advanced myeloid neoplasia.

Invest New Drugs 2015 Apr 9;33(2):371-9. Epub 2014 Dec 9.

Department of Medicine, The University of Chicago, Chicago, IL, USA,

Background We hypothesized that targeting two mechanisms of epigenetic silencing would be additive or synergistic with regard to expression of specific target genes. The primary objective of the study was to establish the maximum tolerated dose (MTD) of belinostat in combination with a fixed dose of azacitidine (AZA). Methods In Part A of the study, patients received a fixed dose of AZA, with escalating doses of belinostat given on the same days 1-5, in a 28 day cycle. Part B was designed to evaluate the relative contribution of belinostat to the combination based on analysis of pharmacodynamic markers, and incorporated a design in which patients were randomized during cycle 1 to AZA alone, or the combination, at the maximally tolerated dose of belinostat. Results 56 patients with myeloid neoplasia were enrolled. Dose escalation was feasible in part A, up to 1000 mg/m(2) dose level of belinostat. In Part B, 18 patients were assessable for quantitative analysis of specific target genes. At day 5 of therapy, MDR1 was significantly up-regulated in the belinostat/AZA arm compared with AZA alone arm (p = 0.0023). There were 18 responses among the 56 patients. Conclusions The combination of belinostat and AZA is feasible and associated with clinical activity. The recommended phase II dose is 1000 mg/m(2) of belinostat plus 75 mg/m(2) of AZA on days 1-5, every 28 days. Upregulation in MDR1 was observed in the combination arm at day 5 compared with the AZA alone arm, suggesting a relative biologic contribution of belinostat to the combination.
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http://dx.doi.org/10.1007/s10637-014-0194-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4390421PMC
April 2015

Microcystic adnexal carcinoma in the axilla of an 18-year-old woman.

Pediatr Dermatol 2014 Nov-Dec;31(6):e145-8

Dermatology Department, Walter Reed National Military Medical Center, Bethesda, Maryland.

Microcystic adnexal carcinoma (MAC) is an uncommon adnexal neoplasm with a predilection for the head and neck. The tumor rarely metastasizes but is locally aggressive and commonly demonstrates perineural invasion. MAC occurs most often in older adults. This report describes a young woman with a MAC in her left axilla who required two stages of Mohs micrographic surgery followed by a wide local excision because of persistent perineural invasion in close proximity to the brachial plexus. Other cases presenting in the pediatric age group are discussed.
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http://dx.doi.org/10.1111/pde.12430DOI Listing
November 2015